Mesocarb

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Mesocarb
Mesocarb.svg
Clinical data
Routes of
administration 		Oral
ATC code
  • none
Legal status
Legal status
Pharmacokinetic data
Metabolism hepatic
Excretion renal
Identifiers
  • 5-(Phenylcarbamoylimino)-3-(1-phenylpropan-2-yl)-5H-1,2,3-oxadiazol-3-ium-2-ide
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
CompTox Dashboard (EPA)
Chemical and physical data
Formula C18H18N4O2
Molar mass 322.368 g·mol−1
3D model (JSmol)
  • O=C(\N=C1/C=[N+](\[N-]O1)C(C)Cc2ccccc2)Nc3ccccc3
  • InChI=1S/C18H18N4O2/c1-14(12-15-8-4-2-5-9-15)22-13-17(24-21-22)20-18(23)19-16-10-6-3-7-11-16/h2-11,13-14H,12H2,1H3,(H,19,23)/b20-17+ Yes check.svgY
  • Key:DMHQLXUFCQSQQQ-LVZFUZTISA-N Yes check.svgY
   (verify)

Mesocarb (brand names Sidnocarb, Sydnocarb) is a drug that is currently being developed for Parkinson's disease. [2]

Contents

The drug was originally developed in the USSR in the 1970s [3] [4] for a variety of indications including asthenia, apathy, adynamia and some clinical aspects of depression and schizophrenia. [5] [6] Mesocarb was used for counteracting the sedative effects of benzodiazepine drugs, [7] increasing workload capacity and cardiovascular function, [8] treatment of ADHD and hyperactivity in children, [9] [10] as a nootropic, [11] and as a drug to enhance resistance to extremely cold temperatures. [12] [13] It is also listed as having antidepressant and anticonvulsant properties.

The drug has been found to act as a selective dopamine reuptake inhibitor by blocking the actions of the dopamine transporter (DAT), [14] [15] and lacks the dopamine release characteristic of stimulants such as dextroamphetamine. [16] [17] [18] It was the most selective DAT inhibitor amongst an array of other DAT inhibitors to which it was compared. [15]

Mesocarb was sold in Russia as 5 milligram tablets under the brand name Sydnocarb. Hydroxylated metabolites can be detected in urine for up to 10 days after consumption. [19]

The drug is almost unknown in the western world and is neither used in medicine nor studied scientifically to any great extent outside Russia and other countries in the former Soviet Union. It has however been added to the list of drugs under international control and is a scheduled substance in most countries, despite its multiple therapeutic applications and reported lack of significant abuse potential. [20]

Mesocarb had erroneously been referred to as a prodrug of amphetamine [21] but this was based on older literature that relied on gas chromatography as an analytical method. Subsequently, with the advent of mass spectroscopy, it has been shown that presence of amphetamine in prior studies was an artifact of gas chromatography method. [22] More recent studies using mass spectroscopy show that negligible levels of amphetamine are released from mesocarb metabolism. [19]

Chemistry

Mesocarb is a mesoionic sydnone imine. It has the amphetamine-backbone present, except that the RN has a complicated imine side-chain present.

Preparation

Patents: Mesocarb synthesis.svg
Patents:

Feprosidnine (Sydnophen) is converted from the hydrochloride salt (1) into the freebase amine (2). This is then treated with phenylisocyanate (3).

Related Research Articles

<span class="mw-page-title-main">Amphetamine</span> Central nervous system stimulant

Amphetamine is a central nervous system (CNS) stimulant that is used in the treatment of attention deficit hyperactivity disorder (ADHD), narcolepsy, and obesity. Amphetamine was discovered as a chemical in 1887 by Lazăr Edeleanu, and then as a drug in the late 1920s. It exists as two enantiomers: levoamphetamine and dextroamphetamine. Amphetamine properly refers to a specific chemical, the racemic free base, which is equal parts of the two enantiomers in their pure amine forms. The term is frequently used informally to refer to any combination of the enantiomers, or to either of them alone. Historically, it has been used to treat nasal congestion and depression. Amphetamine is also used as an athletic performance enhancer and cognitive enhancer, and recreationally as an aphrodisiac and euphoriant. It is a prescription drug in many countries, and unauthorized possession and distribution of amphetamine are often tightly controlled due to the significant health risks associated with recreational use.

<span class="mw-page-title-main">Stimulant</span> Drug that increases activity of central nervous system

Stimulants are a class of drugs that increase the activity of the brain and the spinal cord. They are used for various purposes, such as enhancing alertness, attention, motivation, cognition, mood, and physical performance. Some of the most common stimulants are caffeine, nicotine, amphetamines, cocaine, and modafinil.

<span class="mw-page-title-main">Methylphenidate</span> Central nervous system stimulant

Methylphenidate, sold under the brand names Ritalin and Concerta among others, is a potent central nervous system (CNS) stimulant used medically to treat attention deficit hyperactivity disorder (ADHD) and, to a lesser extent, narcolepsy. It is a primary medication for ADHD ; it may be taken by mouth or applied to the skin, and different formulations have varying durations of effect, commonly ranging from 2-4 hours. For ADHD, the effectiveness of methylphenidate is comparable to atomoxetine but modestly lower than amphetamines.

Stimulant psychosis is a mental disorder characterized by psychotic symptoms. It involves and typically occurs following an overdose or several day binge on psychostimulants; however, one study reported occurrences at regularly prescribed doses in approximately 0.1% of individuals within the first several weeks after starting amphetamine or methylphenidate therapy. Methamphetamine psychosis, or long-term effects of stimulant use in the brain, depend upon genetics and may persist for some time.

<span class="mw-page-title-main">Dexmethylphenidate</span> CNS Stimulant

Dexmethylphenidate, sold under the brand name Focalin among others, is a potent central nervous system (CNS) stimulant used to treat attention deficit hyperactivity disorder (ADHD) in those over the age of five years. It is taken by mouth. The immediate release formulation lasts up to five hours while the extended release formulation lasts up to twelve hours. It is the more active enantiomer of methylphenidate.

<span class="mw-page-title-main">Phenylpiracetam</span> Chemical compound

Phenylpiracetam, is a phenylated analog of the drug piracetam. It was developed in 1983 as a medication for Soviet Cosmonauts to treat the prolonged stresses of working in space. Phenylpiracetam was created at the Russian Academy of Sciences Institute of Biomedical Problems in an effort led by psychopharmacologist Valentina Ivanovna Akhapkina. In Russia it is now available as a prescription drug. Research on animals has indicated that phenylpiracetam may have anti-amnesic, antidepressant, anticonvulsant, anxiolytic, and memory enhancement effects.

<span class="mw-page-title-main">Dopaminergic</span> Substance related to dopamine functions

Dopaminergic means "related to dopamine" (literally, "working on dopamine"), dopamine being a common neurotransmitter. Dopaminergic substances or actions increase dopamine-related activity in the brain. Dopaminergic brain pathways facilitate dopamine-related activity. For example, certain proteins such as the dopamine transporter (DAT), vesicular monoamine transporter 2 (VMAT2), and dopamine receptors can be classified as dopaminergic, and neurons that synthesize or contain dopamine and synapses with dopamine receptors in them may also be labeled as dopaminergic. Enzymes that regulate the biosynthesis or metabolism of dopamine such as aromatic L-amino acid decarboxylase or DOPA decarboxylase, monoamine oxidase (MAO), and catechol O-methyl transferase (COMT) may be referred to as dopaminergic as well. Also, any endogenous or exogenous chemical substance that acts to affect dopamine receptors or dopamine release through indirect actions (for example, on neurons that synapse onto neurons that release dopamine or express dopamine receptors) can also be said to have dopaminergic effects, two prominent examples being opioids, which enhance dopamine release indirectly in the reward pathways, and some substituted amphetamines, which enhance dopamine release directly by binding to and inhibiting VMAT2.

<span class="mw-page-title-main">4-Hydroxyamphetamine</span> Group of stereoisomers

4-Hydroxyamphetamine (4HA), also known as hydroxyamfetamine, hydroxyamphetamine, oxamphetamine, norpholedrine, para-hydroxyamphetamine, and α-methyltyramine, is a drug that stimulates the sympathetic nervous system.

<span class="mw-page-title-main">Lisdexamfetamine</span> Central nervous system stimulant prodrug

Lisdexamfetamine, sold under the brand names Vyvanse and Elvanse among others, is a stimulant medication that is used to treat attention deficit hyperactivity disorder (ADHD) in children and adults and for moderate-to-severe binge eating disorder in adults. Lisdexamfetamine is taken by mouth. Its effects generally begin within two hours and last for up to 14 hours. In the United Kingdom, it is usually less preferred to methylphenidate for the treatment of children.

<span class="mw-page-title-main">Feprosidnine</span> Chemical compound

Feprosidnine (Sydnophen) is a stimulant drug which was developed in the USSR in the 1970s. It is structurally related to another Russian drug mesocarb but unlike mesocarb, was withdrawn earlier from production. In comparison with mesocarb it has own antidepressant activity, which makes it useful in treating depressions. Indications of feprosidnine included apathic, asthenic depressions, fatigue, apathic syndrome, narcolepsy and other similar conditions. Therapeutic range of doses: 10-50mg a day. Sydnophen has multiple mechanisms of action, the relative importance of which has not been clearly established. Effects on the body include reversible monoamine oxidase inhibition, cholinergic, adrenergic, opioid and nitric oxide donating actions, all of which may contribute to its pharmacological effects to some extent.

<span class="mw-page-title-main">Bromantane</span> Stimulant drug

Bromantane, sold under the brand name Ladasten, is an atypical psychostimulant and anxiolytic drug of the adamantane family related to amantadine and memantine which is used in Russia in the treatment of neurasthenia. Although the effects of the bromantane have been determined to be dependent on the dopaminergic and possibly serotonergic neurotransmitter systems, its exact mechanism of action is unknown, and it is distinct in its properties relative to typical psychostimulants such as amphetamine. Because of its unique aspects, bromantane has sometimes been described instead as an actoprotector.

<span class="mw-page-title-main">Selank</span> Chemical compound

Selank is a nootropic, anxiolytic peptide based drug developed by the Institute of Molecular Genetics of the Russian Academy of Sciences. Selank is a heptapeptide with the sequence Thr-Lys-Pro-Arg-Pro-Gly-Pro (TKPRPGP). It is a synthetic analogue of human tuftsin.

<span class="mw-page-title-main">Pipofezine</span> Chemical compound

Pipofezine, sold under the brand name Azafen or Azaphen, is a tricyclic antidepressant approved in Russia for the treatment of depression. It was introduced in the late 1960s and is still used today.

<span class="mw-page-title-main">Echinopsidine</span> Chemical compound

Echinopsidine (Adepren) is an antidepressant that was under development in Bulgaria for the treatment of depression. It increases serotonin, norepinephrine, and dopamine levels in the brain and is believed to act as a monoamine oxidase inhibitor (MAOI). Echinopsidine is found naturally in Echinops echinatus along with the related alkaloids echinopsine and echinozolinone.

<span class="mw-page-title-main">Emoxypine</span> Chemical compound

Emoxypine (2-ethyl-6-methyl-3-hydroxypyridine), also known as Mexidol or Mexifin, a succinate salt, is chemical compound which is claimed by its manufacturer, the Russian company Pharmasoft Pharmaceuticals, to have antioxidant and actoprotector properties.

<span class="mw-page-title-main">Benzobarbital</span> Chemical compound

Benzobarbital (Benzonal) is a barbiturate derivative. It has anticonvulsant effects and has been used for the treatment of epilepsy.

<span class="mw-page-title-main">Semax</span> Chemical compound

Semax is a drug which is used mostly in Russia for a broad range of conditions but predominantly for its purported nootropic, neuroprotective, and neurorestorative properties. Semax has not been evaluated, approved for use, or marketed in most other countries. It is prescribed in eastern Europe and Russia for brain trauma.

<span class="mw-page-title-main">Temgicoluril</span> Anxiolytic medication

Temgicoluril, also known as tetramethylglycoluril and sold under the brand names Adaptol and Mebicar, is an anxiolytic medication produced by Latvian pharmaceutical company Olainfarm and sold in Latvia and Russia.

Actoprotectors or synthetic adaptogens are compounds that enhance an organism's resilience to physical stress without increasing heat output. Actoprotectors are distinct from other performance-enhancing substances in that they increase physical and psychological resilience via non-exhaustive action. The term "actoprotector" is used to describe synthetic and isolated compounds possessing adaptogenic properties. By contrast, the term "adaptogen" is most often use to describe a natural herb as a whole, which can contain hundreds if not thousands of biologically active components.

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References

  1. ↑ Anvisa (2023-03-31). "RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial" [Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control] (in Brazilian Portuguese). Diário Oficial da União (published 2023-04-04). Archived from the original on 2023-08-03. Retrieved 2023-08-16.
  2. ↑ "Melior Discovery Announces Spinout of Melior Pharmaceuticals II, LLC". 10 May 2016.
  3. ↑ GB Patent 1262830 - NOVEL SYDNONIMINE DERIVATIVE
  4. ↑ Anokhina IP, Zabrodin GD, Svirinovskiĭ I (1974). "[Characteristics of the central action of sidnocarb]" [Characteristics of the central action of sidnocarb]. Zhurnal Nevropatologii I Psikhiatrii Imeni S.S. Korsakova (in Russian). 74 (4): 594–602. PMID   4825943.
  5. ↑ Rudenko GM, Altshuler RA (1979). "Peculiarities of clinical activity and pharmacokinetics of sydnocarb (sydnocarbum), an original psychostimulant". Agressologie. 20 (D): 265–270. PMID   45391.
  6. ↑ Witkin JM, Savtchenko N, Mashkovsky M, Beekman M, Munzar P, Gasior M, et al. (March 1999). "Behavioral, toxic, and neurochemical effects of sydnocarb, a novel psychomotor stimulant: comparisons with methamphetamine". The Journal of Pharmacology and Experimental Therapeutics. 288 (3): 1298–1310. PMID   10027871.
  7. ↑ Valueva LN, Tozhanova NM (1982). "[Sidnocarb correction of the adverse effects of benzodiazepine tranquilizers]" [Sidnocarb correction of the adverse effects of benzodiazepine tranquilizers]. Zhurnal Nevropatologii I Psikhiatrii Imeni S.S. Korsakova (in Russian). 82 (8): 92–97. PMID   6127851.
  8. ↑ Vinar O, Klein DF, Potter WZ, Gause EM (December 1991). "A survey of psychotropic medications not available in the United States". Neuropsychopharmacology. 5 (4): 201–217. PMID   1804161.
  9. ↑ Turova NF, Misionzhnik EI, Ermolina LA, Aziavchik AV, Krasov VA (1988). "[Excretion of monoamines, their precursors and metabolites in the hyperactivity syndrome in mentally defective children]" [Excretion of monoamines, their precursors and metabolites in the hyperactivity syndrome in mentally defective children]. Voprosy Meditsinskoi Khimii (in Russian). 34 (1): 47–50. PMID   3369126.
  10. ↑ Krasov VA (1988). "[Sidnocarb treatment of young schoolchildren with the hyperdynamic syndrome]" [Sidnocarb treatment of young schoolchildren with the hyperdynamic syndrome]. Zhurnal Nevropatologii I Psikhiatrii Imeni S.S. Korsakova (in Russian). 88 (8): 97–101. PMID   3195293.
  11. ↑ Ganiev MM, Kharlamov AN, Raevskiĭ KS, Guseĭnov DI (October 1987). "[Effect of sidnocarb on learning and memory]" [Effect of sidnocarb on learning and memory]. Biulleten' Eksperimental'noi Biologii I Meditsiny (in Russian). 104 (10): 453–454. PMID   3676468.
  12. ↑ Barer AS, Lakota NG, Ostrovskaia GZ, Shashkov VS (Nov–Dec 1988). "[Pharmacologic correction of the effect of cold on man]" [Pharmacologic correction of the effect of cold on man]. Kosmicheskaia Biologiia I Aviakosmicheskaia Meditsina (in Russian). 22 (6): 66–73. PMID   2906380.
  13. ↑ Levina MN, Badyshtov BA, Gan'shina TS (2006). "[Thermoprotector properties of a combination of sydnocarb with ladasten]" [Thermoprotector properties of a combination of sydnocarb with ladasten]. Eksperimental'naia i Klinicheskaia Farmakologiia (in Russian). 69 (1): 71–73. PMID   16579065.
  14. ↑ Erdö SL, Kiss B, Rosdy B (1981). "Inhibition of dopamine uptake by a new psychostimulant mesocarb (Sydnocarb)". Polish Journal of Pharmacology and Pharmacy. 33 (2): 141–147. PMID   7312716.
  15. 1 2 Gruner JA, Mathiasen JR, Flood DG, Gasior M (May 2011). "Characterization of pharmacological and wake-promoting properties of the dopaminergic stimulant sydnocarb in rats". The Journal of Pharmacology and Experimental Therapeutics. 337 (2): 380–390. doi:10.1124/jpet.111.178947. PMID   21300706. S2CID   9985668.
  16. ↑ Afanas'ev II, Anderzhanova EA, Kudrin VS, Rayevsky KS (2001). "Effects of amphetamine and sydnocarb on dopamine release and free radical generation in rat striatum". Pharmacology, Biochemistry, and Behavior. 69 (3–4): 653–658. doi:10.1016/S0091-3057(01)00574-3. PMID   11509228. S2CID   32739707.
  17. ↑ Anderzhanova EA, Afanas'ev II, Kudrin VS, Rayevsky KS (September 2000). "Effect of d-amphetamine and sydnocarb on the extracellular level of dopamine, 3,4-dihydroxyphenylacetic acid, and hydroxyl radicals generation in rat striatum". Annals of the New York Academy of Sciences. 914 (1): 137–145. Bibcode:2000NYASA.914..137A. doi:10.1111/j.1749-6632.2000.tb05191.x. PMID   11085316. S2CID   12326076.
  18. ↑ Gainetdinov RR, Sotnikova TD, Grekhova TV, Rayevsky KS (December 1997). "Effects of a psychostimulant drug sydnocarb on rat brain dopaminergic transmission in vivo". European Journal of Pharmacology. 340 (1): 53–58. doi:10.1016/S0014-2999(97)01407-6. PMID   9527506.
  19. 1 2 Shpak AV, Appolonova SA, Semenov VA (January 2005). "Validation of liquid chromatography-electrospray ionization ion trap mass spectrometry method for the determination of mesocarb in human plasma and urine". Journal of Chromatographic Science. 43 (1): 11–21. doi: 10.1093/chromsci/43.1.11 . PMID   15808002.
  20. ↑ Rudenko GM, Altshuler RA (1978). "[Experimental and clinical study of Sydnocarb]". Hung Pharmacotherapy (in Russian). 124: 150–4.
  21. ↑ Dettmeyer R, Verhoff MA, Schütz HF (9 October 2013). Forensic Medicine: Fundamentals and Perspectives. Springer Science & Business Media. pp. 519–. ISBN   978-3-642-38818-7.
  22. ↑ Appolonova SA, Shpak AV, Semenov VA (February 2004). "Liquid chromatography-electrospray ionization ion trap mass spectrometry for analysis of mesocarb and its metabolites in human urine". Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences. 800 (1–2): 281–289. doi:10.1016/j.jchromb.2003.10.071. PMID   14698267.
  23. ↑ Michail D. Maschkovskij, 6 More », DE2028880 (1979 to Vsesojuznyj Nautschno-Issledovatelskij Chimiko-Farmacevtitscheskij Institut Imeni Sergo Ordschonikidze, Moskau).
  24. ↑ Mikhail Davidovich Mashkovsky, et al. GB1262830 (1972 to Vni Khim Farmatsevtichesky I I).
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